A contraceptive vaccine would provide a simple strategy for women and families to gain control of their reproductive lives and prevent undesired pregnancy. Development of a successful contraceptive vaccine requires the ability to generate immune responses in the genital tract. In order for this work to progress we must define the best technique for generating genital tract immunity. The reproductive physiology and anatomy of rhesus macaques is remarkably similar to humans. Little work has been done to define the normal immune system of the genital tract in women and nonhuman primates. It is clear that local immune responses to vaginally administered antigens occur in women and rhesus macaques and that the cellular components of a local immune system are present in the lower genital tract of both women and rhesus macaques. Recently, we have made considerable advances in the understanding of female genital tract immunology by studying the rhesus macaque. The techniques and assays in our laboratory can be easily adapted to assist in the effort to elicit strong immunity to a contraceptive vaccine. In the proposed studies, the antigens we will use for immunization will include irrelevant antigens such as tetanus toxoid and cholera toxin, and relevant antigens such as the sperm surface protein PH-20. The irrelevant antigens will be used because we have extensive experience with the immune response of monkeys to these antigens and they will serve as a useful baseline to gauge immune responses to PH-20. In addition, we will use other antigens which could prove to be useful as contraceptive vaccines as they are developed by other members of this Center. Experiments with contraceptive vaccines based on sperm antigens have demonstrated that it can be straightforward to produce effective immunity in rodents. However, current studies in nonhuman primates have resulted in only moderate immune responses to the same antigens. A major goal of this project is to determine if the timing of immunization in relation to the menstrual cycle affects genital tract immune responses in rhesus macaques. Further, we will determine if administration of exogenous steroid hormones can strengthen and direct the immune response to mucosal sites. The overall goal of this project is to develop novel immunization strategies designed to produce strong immune responses in the genital tract of nonhuman primates.